PROJECT SUMMARY/ABSTRACT Acute respiratory distress syndrome (ARDS) is characterized by acute onset of diffuse, bilateral pulmonary edema and severe hypoxemia not fully explained by cardiac failure. The syndrome affects 45,000 children in the United States annually, representing 10% of mechanically ventilated children in pediatric intensive care units (PICUs), with an associated mortality rate of up to 20%. There are no specific pharmacological therapies for ARDS despite several trials, and supportive care remains the mainstay of treatment. In children, a lack of therapies is further compounded by uncertainty in management, as guidelines are typically extrapolated from adult ARDS, with uncertain applicability. However, pediatric ARDS possesses a distinct epidemiologic and outcome profile, necessitating studies specific to this population. Given the heterogeneity of ARDS, biomarkers have been proposed to aid in diagnosis, improve risk stratification, and identify endogenous sub- phenotypes (endotypes) with shared pathophysiologic, biomarker, or transcriptomic profiles. Risk stratification and endotype identification are essential for improved patient selection for trials of targeted therapies, particularly for targeted therapies beyond supportive care. However, the absence of well-powered cohorts with biomarker data leaves a knowledge gap regarding the existence and clinical relevance of endotypes in pediatric ARDS. This proposal builds off of Dr. Yehya?s experience with plasma biomarkers and whole blood transcriptomics in pediatric ARDS obtained during his K23 award to perform prospective risk stratification and endotype identification in 500 children with ARDS from 12 PICUs in the United States. The specific goals are to 1) validate PARDSEVERE, a multiple biomarker-based risk stratification tool in pediatric ARDS; 2) test whether a known 100-gene classifier identifies transcriptomic endotypes in pediatric ARDS; and 3) use clustering methodology to identify novel plasma biomarker- and mRNA-based endotypes. These studies are the first steps towards prognostic enrichment (selecting subjects with worse prognosis for trials) and predictive enrichment (selecting subjects likely to respond to a trial intervention) for future pediatric ARDS trials. The proposed studies will validate a risk stratification tool for pediatric ARDS and identify endotypes with shared biology in order to more appropriately target therapies in future trials. The proposal leverages the existing infrastructure and extensive expertise at the Children?s Hospital of Philadelphia, the University of Pennsylvania, and Cincinnati Children?s Hospital Medical Center. Overall, these studies are a significant advance for the field of pediatric ARDS, represent a tremendous resource for future studies, and form the basis for the next generation of interventional trials using enrichment strategies to mitigate heterogeneity.